Role of RET-Regulated GDNF-GFRα1 Endocytosis in Methamphetamine-Induced Neurotoxicity

TL;DR

This study explores how the RET-regulated GDNF-GFRα1 endocytosis protects against methamphetamine-induced brain damage and suggests targeting this pathway as a potential treatment.

Contribution

The study identifies RET as a key molecule in methamphetamine-induced disruption of GDNF-mediated neuroprotection.

Findings

METH exposure increases apoptosis and GDNF expression in hippocampal cells.

METH impairs GDNF-GFRα1 endocytosis and reduces RET expression in hippocampal cells.

Overexpression of RET mitigates METH-induced cell degeneration and apoptosis.

Abstract

Methamphetamine (METH) is a highly addictive synthetic psychostimulant that can induce severe neurotoxicity, leading to neurodegeneration similar to neurodegenerative diseases. The endocytosis of glial cell line-derived neurotrophic factor (GDNF) and its family receptor alpha 1 (GFRα1), regulated by transmembrane receptor tyrosine kinase (RET), has been shown to resist neurodegeneration. Specifically, the endocytosis of GDNF-GFRα1 mediated by RET is crucial in protecting neurons. Although many molecular mechanisms of METH induced neurotoxicity have been explored, the obstacles to the neuroprotective effect of GDNF in the context of METH induced neurotoxicity are still unclear. In this study, an increase in cell apoptosis and GDNF expression was observed in the hippocampus of METH abusers. METH also induces cell degeneration, cytotoxicity, and GDNF expression and release in hippocampal neuronal (HT-22) cells in a concentration-dependent manner (0.25, 0.5, 1, 2, and 4 mM) and time-dependent manner (3, 6, 12, 24, and 48 h). Meanwhile, after 24 h of exposure to METH (2mM), apoptosis, impaired endocytosis of GDNF-GFRα1, and decreased expression of RET were observed in HT-22 cells and organotypic hippocampal slices of mice. More notably, overexpression of RET weakened METH induced cell degeneration, apoptosis, and disruption of GDNF-GFRα1 endocytosis in HT-22 cells. This study suggests that RET is a key molecule for METH to disrupt GDNF-mediated neuroprotective signaling, and targeting RET-mediated endocytosis of GDNF-GFRα1 may be a potential therapeutic approach for METH induced neurotoxicity and neurodegeneration.

Figures